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A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable

Nature volume 478, pages 255–259 (2011)Cite this article

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A Corrigendum to this article was published on 01 February 2012

Abstract

The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base1. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base2. However, the relative functions of these two pools and their interrelationship are not understood. Here we specifically ablated Lgr5-expressing cells in mice using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus. We found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Our results demonstrate that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. These data provide the first experimental evidence for the interrelationship between these populations. The Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under non-pathological conditions.

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Figure 1: Characterization of DT-mediated CBC ablation.
Figure 2: Maintenance of normal crypt architecture is not mediated by Lgr5 -positive cells that have escaped ablation.
Figure 3: Bmi1 -expressing stem cells are mobilized to compensate for the loss of Lgr5 -expressing CBCs.
Figure 4: Bmi1- expressing cells give rise to Lgr5- expressing CBCs under normal and injury conditions.

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Acknowledgements

We gratefully acknowledge efforts by all the members of the Genentech mouse facility, in particular R. Ybarra and G. Morrow. We are grateful to N. Strauli, D.-K. Tran and A. Rathnayake for assistance with mouse breeding. We thank M. Roose-Girma, X. Rairdan and the members of the embryonic stem cell and microinjection groups for embryonic stem cell work and transgenic line generation and members of the F.J.d.S. laboratory for discussions and ideas. This work was funded in part by the National Institutes of Health through the NIH Director’s New Innovator Award Program, 1-DP2-OD007191 and by R01-DE021420, both to O.D.K.

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Authors and Affiliations

  1. Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Hua Tian, Søren Warming & Frederic J. de Sauvage

  2. Departments of Orofacial Sciences and Pediatrics, Institute for Human Genetics and Program in Craniofacial and Mesenchymal Biology, UCSF, 513 Parnassus Avenue, San Francisco, California 94143-0442, USA,

    Brian Biehs & Ophir D. Klein

  3. Department of Research Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Kevin G. Leong

  4. Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Linda Rangell

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  1. Hua Tian
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Contributions

H.T., B.B., S.W., K.G.L. and L.R. designed, performed experiments and collected data. H.T., B.B., O.D.K. and F.J.d.S. designed experiments, analysed the data and wrote the manuscript. O.D.K. and F.J.d.S. are joint senior authors. All authors discussed results and edited the manuscript.

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Correspondence to Ophir D. Klein or Frederic J. de Sauvage.

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Competing interests

H.T., S.W., K.G.L., L.R. and F.J.d.S. are employees of Genentech Inc., a member of the Roche Group, and may have an equity interest in Roche.

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Tian, H., Biehs, B., Warming, S. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011). https://doi.org/10.1038/nature10408

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